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EP-4739652-A1 - LIPIDS AND COMPOSITIONS THEREOF

EP4739652A1EP 4739652 A1EP4739652 A1EP 4739652A1EP-4739652-A1

Abstract

The present disclosure relates to cationic and/or ionizable lipids and nucleic acid-lipid particle compositions comprising the same. The present disclosure also relates to methods of using and delivering the described lipids and lipid-containing particles.

Inventors

  • LANDIS, Ryan F.
  • BHAT, BALKRISHEN
  • XU, Jieni
  • OZDEMIR, Cafer
  • YILMAZ, Burak
  • ERKUL, Yusuf
  • KRAUS, MANFRED

Assignees

  • Kernal Biologics, Inc.

Dates

Publication Date
20260513
Application Date
20240702

Claims (20)

  1. CLAIMS WHAT IS CLAIMED IS: 1. A compound of Formula I’: Formula I’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein: L 1 is substituted or unsubstituted linear -C 3 - 12 alkylene or -C 3-12 alkenylalkylene; L 2 is substituted or unsubstituted linear -C 4-12 alkylene or -C 3-12 alkenylalkylene; L 3 is substituted or unsubstituted linear -C 4-12 alkylene or -C 3-12 alkenylalkylene; wherein if L 1 , L 2 , or L 3 is substituted, then L 1 , L 2 , or L 3 is substituted with 1-5 substituents selected from the group consisting of halogen, deuterium, -CN, linear or branched C 1-10 alkyl, linear or branched C 1-10 heteroalkyl, C 1-2 haloalkyl, -C(=O)R 10 , -C(=O)N(R 10 ) 2 , - OR 10 , -N(R 10 ) 2 , substituted or unsubstituted C 3-6 cycloalkyl, and substituted or unsubstituted 3- to 10-membered heterocycloalkyl; wherein each substituted C 3-6 cycloalkyl and substituted 3- to 10-membered heterocycloalkyl is substituted with 1-5 R 11 ; L 4 is substituted or unsubstituted -C 1 - 24 alkylene or -C 3-24 alkenylalkylene; wherein L 4 is optionally substituted with 1 to 10 R 11 ; X 1 is a covalent bond, -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O-; X 2 is a covalent bond, -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O-; each R 1 , R 2 , and R 3 , is independently hydrogen, deuterium, halogen, -CN, -OR 10 , -N(R 10 ) 2 , branched C 3-10 alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; provided that at least one of R 1 , R 2 , and R 3 is not hydrogen or deuterium; or when each R 1 , R 2 , and R 3 is hydrogen, or deuterium, then at least one of L 1 , L 2 , L 3 is substituted with 1-5 substituents, and at least one of the substituents is not a linear C 1-10 alkyl substituted at a terminal carbon, or a deuterium; R 4 is halogen, -OH, -OR 10 , -O-C(=O)-R 10 , -C(=O)-OR 10 , -O-C(=O)-OR 10 -, -C(=O)-O-C(=O)- R 10 , -O-C(=O)-C 0 - 9 alkylene-R 11 , -(O-C 0 - 9 alkylene-) n R 11 , -O-C(=O)-C 0 - 9 alkylene- N(R 10 ) 2 , -N(R 10 ) 2 , or -C(=O)-C 0 - 9 alkylene-N(R 10 ) 2 ; each R 5, R 6 , R 7 , R 8 , or R 9 is independently hydrogen, deuterium, halogen, -CN, -OR 10 , -N(R 10 ) 2 , -O-C(=O)-R 10 , C 1-10 alkyl, C 1-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; each R 10 is independently hydrogen, C 1-10 alkyl, C 1-10 heteroalkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; each R 11 is independently hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 1-10 heteroalkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)OH, - C(O)-O-C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl) 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OH, -O-C 1-6 alkyl, -SH, -S(C 1-6 alkyl), - S(O)(C 1-6 alkyl), -S(O) 2 (C 1-6 alkyl), or -S(O) 2 NH(C 1-6 alkyl); n is an integer from 0 - 20; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, 2, 3, 4, or 5; and r is 0 or 1. 2. The compound of claim 1, wherein r is 0. 3. The compound of claim 1 or 2, wherein X 1 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)- N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O- and X 2 is -C(=O)-O-, -O-C(=O)-, -O- C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O. 4. A compound of Formula I: Formula I or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein: L 1 is substituted or unsubstituted linear -C 3 - 12 alkylene or -C 3-12 alkenylalkylene; L 2 is substituted or unsubstituted linear -C 4-12 alkylene or -C 3-12 alkenylalkylene; L 3 is substituted or unsubstituted linear -C 4-12 alkylene or -C 3-12 alkenylalkylene; wherein if L 1 , L 2 , or L 3 is substituted, then L 1 , L 2 , or L 3 is substituted with 1-5 substituents selected from the group consisting of halogen, deuterium, -CN, linear or branched C 1-10 alkyl, linear or branched C 1-10 heteroalkyl, C 1-2 haloalkyl, -C(=O)R 10 , -C(=O)N(R 10 ) 2 , - OR 10 , -N(R 10 ) 2 , substituted or unsubstituted C 3-6 cycloalkyl, and substituted or unsubstituted 3- to 10-membered heterocycloalkyl; wherein each substituted C 3-6 cycloalkyl and substituted 3- to 10-membered heterocycloalkyl is substituted with 1-5 R 11 ; L 4 is substituted or unsubstituted -C 1 - 24 alkylene or -C 3-24 alkenylalkylene; wherein L 4 is optionally substituted with 1 to 10 R 11 ; X 1 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O-; X 2 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O-; each R 1 , R 2 , and R 3 , is independently hydrogen, deuterium, halogen, -CN, -OR 10 , -N(R 10 ) 2 , branched C 3-10 alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; provided that at least one of R 1 , R 2 , and R 3 is not hydrogen or deuterium; or when each R 1 , R 2 , and R 3 is hydrogen, or deuterium, then at least one of L 1 , L 2 , L 3 is substituted with 1-5 substituents, and at least one of the substituents is not a linear C 1-10 alkyl substituted at a terminal carbon, or a deuterium; R 4 is -OH, -OR 10 , -O-C(=O)-R 10 , -C(=O)-OR 10 , -O-C(=O)-OR 10 -, -C(=O)-O-C(=O)-R 10 , -O- C(=O)-C 0 - 9 alkylene-R 11 , -(O-C 0 - 9 alkylene-) n R 11 , -O-C(=O)-C 0 - 9 alkylene-N(R 10 ) 2 , - N(R 10 ) 2 , or -C(=O)-C 0 - 9 alkylene-N(R 10 ) 2 ; each R 5, R 6 , R 7 , R 8 , or R 9 is independently hydrogen, deuterium, halogen, -CN, -OR 10 , -N(R 10 ) 2 , -O-C(=O)-R 10 , C 1-10 alkyl, C 1-10 heteroalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; each R 10 is independently hydrogen, C 1-10 alkyl, C 1-10 heteroalkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; each R 11 is independently hydrogen, deuterium, halogen, -CN, C 1-10 alkyl, C 1-10 heteroalkyl, C 1-10 haloalkyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C(O)OH, - C(O)-O-C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl) 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OH, -O-C 1-6 alkyl, -SH, -S(C 1-6 alkyl), - S(O)(C 1-6 alkyl), -S(O) 2 (C 1-6 alkyl), or -S(O) 2 NH(C 1-6 alkyl); n is an integer from 0 - 20; p is 0, 1, 2, 3, 4, or 5; and q is 0, 1,
  2. 2,
  3. 3,
  4. 4, or 5.
  5. 5. The compound of any one of claims 1-4, wherein each R 5, R 6 , R 7 , R 8 , or R 9 is independently hydrogen, deuterium, halogen, -CN, -OR 10 , or C 1-10 alkyl.
  6. 6. The compound of any one of claims 1-4, wherein each R 5, R 6 , R 7 , R 8 , or R 9 is independently hydrogen, deuterium, halogen, methyl, ethyl, or isopropyl.
  7. 7. The compound of any one of claims 1-6, having the structure of Formula II: Formula II or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein: L 1 is substituted or unsubstituted linear -C 3 - 12 alkylene; L 2 is substituted or unsubstituted linear -C 4-12 alkylene; L 3 is substituted or unsubstituted linear -C 4-12 alkylene; wherein if L 1 , L 2 , or L 3 is substituted, then L 1 , L 2 , or L 3 is substituted with 1-5 substituents selected from the group consisting of halogen, deuterium, -CN, linear or branched C 1-6 alkyl, C 1-2 haloalkyl, -C(=O)R 10 , -C(=O)N(R 10 ) 2 , -OR 10 , -N(R 10 ) 2 , substituted or unsubstituted C 3-6 cycloalkyl, and substituted or unsubstituted 3- to 6-membered heterocycloalkyl; wherein each substituted C 3-6 cycloalkyl and substituted 3- to 6- membered heterocycloalkyl is substituted with 1-5 R 11 ; L 4 is substituted or unsubstituted -C 1 - 24 alkylene-; wherein L 4 is optionally substituted with 1 to 10 R 11 ; X 1 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O-; X 2 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, -N(R 10 )-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O-; each R 1 , R 2 , and R 3 , is independently hydrogen, deuterium, halogen, -CN, -OR 10 , -N(R 10 ) 2 , branched C 3-10 alkyl, C 3-10 cycloalkyl, C 2-6 alkenyl, or C 2-6 alkynyl; provided that at least one of R 1 , R 2 , and R 3 is not hydrogen or deuterium; or when each R 1 , R 2 , and R 3 is hydrogen or deuterium, then at least one of L 1 , L 2 , L 3 is substituted with 1-5 substituents, and at least one of the substituents is not a linear C 1-10 alkyl substituted at a terminal carbon, or a deuterium; R 4 is -OH, -OR 10 , -O-C(=O)-R 10 , -C(=O)-OR 10 , -O-C(=O)-OR 10 -, -C(=O)-O-C(=O)-R 10 , -O- C(=O)-C 0 - 9 alkylene-R 11 , -(O-C 0 - 9 alkylene-) n R 11 , -O-C(=O)-C 0 - 9 alkylene-N(R 10 ) 2 , - N(R 10 ) 2 , -CH(CH 3 )-CH 2 -OH, or -C(=O)-C 0 - 9 alkylene-N(R 10 ) 2 ; each R 10 is independently hydrogen, C 1-10 alkyl, C 1-10 heteroalkyl, C 1-10 haloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 3-10 cycloalkyl; each R 11 is independently selected from the group consisting of hydrogen, deuterium, halogen, - CN, -C 1-6 alkyl, C 1-10 heteroalkyl, C 1-10 haloalkyl, C 3-10 heterocycloalkyl, C 2-6 alkenyl, C 2- 6 alkynyl, -C(O)OH, -C(O)-O-C 1-6 alkyl, -C(O)-C 1-6 alkyl, -C(O)NH 2 , -C(O)NH(C 1-6 alkyl), -C(O)N(C 1-6 alkyl) 2 , -NH 2 , -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -OH, -O-C 1-6 alkyl, - SH, -S(C 1-6 alkyl), -S(O)(C 1-6 alkyl), -S(O) 2 (C 1-6 alkyl), or -S(O) 2 NH(C 1-6 alkyl); n is an integer from 0 - 20; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, or 4.
  8. 8. The compound of any one of claims 1-78, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein X 1 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, or -N(R 10 )- C(=O)-.
  9. 9. The compound of any one of claims 1-8, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein X 2 is -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R 10 )-, or -N(R 10 )- C(=O)-.
  10. 10. The compound of any one of claims 1-9, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, 3, or 4; and q is 1, 2, 3, or 4.
  11. 11. The compound of any one of claims 1-10, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, or 3; and q is 1, 2, or 3.
  12. 12. The compound of any one of claims 1-10, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein p is 1, and q is 1.
  13. 13. The compound of any one of claims 1-10, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein p is 1, and q is 3.
  14. 14. The compound of any one of claims 1-10, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein p is 3, and q is 1.
  15. 15. The compound of any one of claims 1-10, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein p is 3, and q is 3.
  16. 16. The compound of any one of claims 1-10, or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein p is 3, and q is 4.
  17. 17. The compound of any one of claims 1-16, having the structure of Formula III: Formula III or its N-oxide, or a pharmaceutically acceptable salt thereof.
  18. 18. The compound of any one of claims 1-16, having the structure of Formula III-a: Formula III-a or its N-oxide, or a pharmaceutically acceptable salt thereof.
  19. 19. The compound of any one of claims 1-16, having the structure of Formula IV: Formula IV or its N-oxide, or a pharmaceutically acceptable salt thereof.
  20. 20. The compound of any one of claims 1-17 and 19, wherein X 1 is -C(=O)-O- or -O-C(=O)-.

Description

LIPIDS AND COMPOSITIONS THEREOF CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No.63/511,824 filed July 3, 2023, the entirety of which is hereby incorporated by reference. BACKGROUND [0002] Lipids are amphiphilic molecules that contain three domains: a polar head group, a hydrophobic tail region and a linker between the two domains. Lipid-containing particles have been used as transport vehicles for therapeutic agents such as nucleic acids, small molecules compounds, and proteins into cells and other intracellular compartments. Cationic lipids, ionizable lipids and other types of lipid have been explored for mRNA delivery . SUMMARY [0003] Although a variety of lipid-containing particle compositions have been demonstrated, there remains a need to improve the safety, efficacy, and specificity of such nanoparticle -based transport vehicles. In some embodiments, a lipid-containing particle compositions as described herein demonstrate improved delivery efficiency. In some embodiments, a lipid -containing particle compositions as described herein demonstrate improved toxicity profiles. In some embodiments, a lipid-containing particle compositions as described herein demonstrate improved tolerability (e.g., liver tolerability). In some embodiments, a lipid-containing particle compositions as described herein comprises a lipid as described herein. Without wishing to be bound by any particular theory, the present disclosure provides an insight that certain modifications on the lipid structure demonstrate improved tolerability (e.g., liver tolerability) while preserving delivery performance. In some embodiments, a structure modification comprises halogenation of an aliphatic chain of a lipid. In some embodiments, a lipid described herein comprises halogen. In some embodiments, a lipid described herein comprises F. Without wishing to be bound by any particular theory, in some embodiments, the present disclosure provides an insight that a lipid comprising halogen (e.g., F) surprisingly demonstrates improved tolerability over an otherwise identical lipid that does not comprise halogen (e.g., F). Described herein, in some aspects, is a compound of Formula I’: Formula I’ or its N-oxide, or a pharmaceutically acceptable salt thereof, wherein: L1 is substituted or unsubstituted linear -C3-12 alkylene or -C3-12 alkenylalkylene; L2 is substituted or unsubstituted linear -C4-12 alkylene or -C3-12 alkenylalkylene; L3 is substituted or unsubstituted linear -C4-12 alkylene or -C3-12 alkenylalkylene; wherein if L1, L2, or L3 is substituted, then L1, L2, or L3 is substituted with 1-5 substituents selected from the group consisting of halogen, deuterium, -CN, linear or branched C1-10 alkyl, linear or branched C1-10 heteroalkyl, C1-2 haloalkyl, -C(=O)R10, -C(=O)N(R10)2, - OR10, -N(R10)2, substituted or unsubstituted C3-6 cycloalkyl, and substituted or unsubstituted 3- to 10-membered heterocycloalkyl; wherein each substituted C3-6 cycloalkyl and substituted 3- to 10-membered heterocycloalkyl is substituted with 1-5 R11; L4 is substituted or unsubstituted -C1-24 alkylene or -C3-24 alkenylalkylene; wherein L4 is optionally substituted with 1 to 10 R11; X1 is a covalent bond, -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R10)-, -N(R10)-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O-; X2 is a covalent bond, -C(=O)-O-, -O-C(=O)-, -O-C(=O)-O-, -C(=O)-N(R10)-, -N(R10)-C(=O)-, S-S, -C(=O)-S-, or -C(C=S)-O-; each R1, R2, and R3, is independently hydrogen, deuterium, halogen, -CN, -OR10, -N(R10)2, branched C3-10 alkyl, C3-10 cycloalkyl, C2-6 alkenyl, or C2-6 alkynyl; provided that at least one of R1, R2, and R3 is not hydrogen or deuterium; or when each R1, R2, and R3 is hydrogen, or deuterium, then at least one of L1, L2, L3 is substituted with 1-5 substituents, and at least one of the substituents is not a linear C1-10 alkyl substituted at a terminal carbon, or a deuterium; R4 is halogen, -OH, -OR10, -O-C(=O)-R10, -C(=O)-OR10, -O-C(=O)-OR10-, -C(=O)-O-C(=O)- R10, -O-C(=O)-C0-9 alkylene-R11, -(O-C0-9 alkylene-)nR11, -O-C(=O)-C0-9 alkylene- N(R10)2, -N(R10)2, or -C(=O)-C0-9 alkylene-N(R10)2; each R5, R6, R7, R8, or R9 is independently hydrogen, deuterium, halogen, -CN, -OR10, -N(R10)2, -O-C(=O)-R10, C1-10 alkyl, C1-10 heteroalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C2-6 alkenyl, or C2-6 alkynyl; each R10 is independently hydrogen, C1-10 alkyl, C1-10 heteroalkyl, C1-10 haloalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C2-6 alkenyl, or C2-6 alkynyl; each R11 is independently hydrogen, deuterium, halogen, -CN, C1-10 alkyl, C1-10 heteroalkyl, C1-10 haloalkyl, C3-10 cycloalkyl, C3-10 heterocycloalkyl, C2-6 alkenyl, C2-6 alkynyl, -C(O)OH, - C(O)-O-C1-6 alkyl, -C(O)-C1-6 alkyl, -C(O)NH2, -C(O)NH(C1-6 alkyl), -C(O)N(C1-6 alkyl)2, -NH2, -NH(C1-6 alkyl), -N(C1-6 alkyl)2, -OH, -O-C1-6 alkyl, -SH, -S(C1-6 alkyl), - S(O)(C1-6 alkyl), -S(O)2(C1-6 alkyl), or -S(O)2NH(C1-6 alkyl); n is an integer from 0 - 20; p is 0,